Overview
This project used the fruit fly as an experimental model to better understand visual disorders in humans caused by diseases of the central nervous system, including Parksinson's Disease and epilepsy. Forms of these diseases are caused by mutations in genes shared by both flies and humans and in each case damage to the visual system ensues. The neuronal responses of fruit flies to light impulses (Steady State Visual Evoked Potential (SSVEP) technique) were recorded as a means of assessing the degree of neuronal damage. It was found that damage was picked up by the SVEP technique earlier than by using “traditional” electroretinograms and that the technique therefore had significant potential both for early diagnosis of the disease in humans and for rapid screening of new drug candidates in the flies.
In October 2012 Parkinson's UK awarded a funded PhD studentship on the Role of dopamine and LRRK2 mutants in the decline of vision worth £88,214.
The results of the project were presented at the November 2012 meeting of Parkinson’s UK in York and have led to negotiations with York Hospital and the pharmaceutical company Lundbeck for a collaboration which would analyse the relationship between genetics and vision in a cohort of PD patients.
Supplies of a LRRK inhibitor have been received from Lundbeck for first in vivo testing and Lundbeck are sponsoring Alex Wade to visit Tunisia with a view to screening a cohort of PD patients that frequently (up to 30%) carry the G2019S mutation. The researchers are in negotiation about the suitability of a patent for using gain control in drug testing in flies and are also discussing the possibility of using this procedure in collaboration with an industrial partner.
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In detail
The goal of this project was to understand better how human vision can be affected by diseases of the central nervous system—for example, epilepsy, Parkinson’s Disease and dementia. In some cases, these diseases can be traced to mutations in a single gene and, remarkably, mutations of the counterparts of these genes in fruit flies (Drosophila) cause conditions that resemble the human disease. The goal was hence to understand the effect that single gene mutations have on neural function in both humans and flies and to use the data acquired to help in diagnosing, understanding, modelling and treating human neurological disease.
A previous study, based on the human Steady State Visual Evoked Potential (SSVEP) technique, to obtain steady-state measurements of visual function in flies, indicated a high degree of functional homology with mammals and humans. From this it could be concluded that any investigations of lesions in Drosophila caused by the expression of disease-related genes are likely to have high relevance to the human condition.
To show that the SSVEP analysis was accurate flies were tested which carried histamine receptor mutations, which is known to cause lesions in the visual system. As was expected, the responses were quite different in the histamine knockouts which lacked the frequency components that were hypothesized as due to neuronal signalling. This verification of the origins of these SSVEP signals makes it straightforward to apply the technique to flies carrying genetic models of human disease.
It is known that amongst epilepsy sufferers, a small number of patients have inherited mutations in the K+/Cl- transporter gene hKCC2. The research conducted on this project uncovered that flies with mutations in the homologous kcc have visual deficits including sudden visual stimuli induced paroxysmal discharges and much stronger spontaneous rhythmic activity than wild-type flies.
The most common cause of inherited Parkinson’s disease (PD) is a mutation, G2019S in the hLRRK2 gene. This mutation may also play a role in many sporadic forms of PD. An examination of flies expressing mutated hLRRK2-G2019S found that steady-state measurements could identify lesions in the visual system long before those seen in “traditional” electroretinograms (and before any movement defects were observed). This data provides the first in vivo model of LRRK2, and one which is amenable to fast throughput screening of LRRK2 inhibitors. The development of the LRRK2 inhibitor drugs is of tremendous importance as the current mainstay of PD treatment, L-DOPA, has a time-limited effectiveness.
In October 2012 Parkinson's UK awarded a funded PhD studentship on the Role of dopamine and LRRK2 mutants in the decline of vision worth £88,214.
The results of all these experiments have already led to ideas for work with both PD and epilepsy patients and negotiations are in progress with York Hospital and Lundbeck for a collaboration which would analyse the relationship between genetics and vision in a cohort of PD patients. The data was presented at the November 2012 meeting of Parkinson’s UK in York and preliminary results have already met with strong interest at a recent presentation on human and animal neural gain control in London.
Supplies of a LRRK inhibitor have been received from Lundbeck for first in vivo testing and Lundbeck are sponsoring Alex Wade to visit Tunisia with a view to screening a cohort of PD patients that frequently (up to 30%) carry the G2019S mutation. The researchers are in negotiation about the suitability of a patent for using gain control in drug testing in flies and are also discussing the possibility of using this procedure in collaboration with an industrial partner.
.jpg "Dopaminergic neurons in the brain of a fruit fly")